Works in Progress

The stomachs of more than half the people on Earth are host to Helicobacter pylori, a corkscrew-shaped microbe that may be mankind's most common bacterial infection. It thrives for decades in a corrosive environment few other bugs can tolerate, and in 10 to 20 percent of infected individuals, the bacterium provokes changes that can result in peptic ulcers or stomach cancer. Genetic studies reveal that H. pylori has plagued human populations for at least 10,000 years. But its days may finally be numbered. And microbiologist Martin Blaser, chairman of the department of medicine at New York University School of Medicine, thinks that is a bad development.

"Everybody's worrying about the greenhouse effect and endangered species," he says. "But it's not just the macrobiology that's changing—our microbiology is changing too. H. pylori is a clear-cut example of that."

In the United States and other developed countries, rates of H. pylori infection have been on the decline for decades, due mostly to antibiotics and improved sanitation. But recent surveys suggest that infection with the microbe may actually protect against cancer of the esophagus, gastroesophageal reflux disease, and asthma—ailments that are on the rise in developed countries. The bacterium may also deter the diarrheal diseases that are a leading killer of young children in developing nations. These conclusions are consistent with a broader public-health perspective called the hygiene hypothesis, which holds that childhood infections may strengthen immunity for life. Those infections, and the dozens of ordinary microbial inhabitants of the human body, have been under siege in the 60 years since penicillin came on the scene. "With modern civilization, H. pylori is disappearing," says Blaser.

Doctors used to think ulcers were an incurable consequence of stress and spicy foods. They prescribed antacids ad nauseam, but relapses were commonplace. Then in 1984, researchers proposed that a newfound bacterium played a primary role in the ruptures. Diagnostic tests were developed by the end of the decade. Now peptic ulcers are treated with a one- or two-week course of antibiotics. Rates of ulcers and gastric cancer had already been in retreat anyway, owing to the decline of their primary agent. "We peptic-ulcer people have put ourselves out of business," says David Graham, a gastroenterologist at the VA Medical Center and Baylor College of Medicine in Houston.

But as H. pylori was vanquished in the gut, it assumed celebrity status in the lab. It's the only bacterium linked with an increased risk of cancer, and it was the first organism for which not one but two complete genome sequences were published. "It's a great system for studying oncogenesis, it's a great system for studying physiology, and it's a great system for studying evolution," Blaser says.

Researchers are fascinated by its method of operation. H. pylori spirals like a drill bit into the mucus layer that coats the stomach wall, while making ammonia to neutralize gastric acid. Then it latches onto cells of the stomach lining, and sometimes it injects a protein that persuades cell scaffolding to construct pedestals to support the invader. Other proteins penetrate cell membranes so that nutrients leak from the gastric wall to nourish H. pylori. Yet another substance rallies immune cells that attack infected tissue, further weakening the stomach's acid-making machinery. The net effect is a chronic inflammation that usually stops short of conspicuous symptoms.

"Their ecology is incredible," says microbial geneticist Doug Berg of the Washington University School of Medicine in St. Louis. "They've somehow tempered their lifestyle so that even though they can cause a lot of damage, they can live there for decades."

The vast majority of H. pylori infections are acquired before the age of 5 by oral contact with the saliva, vomit, or feces of infected family members. The bacterium seems to be the only persistent inhabitant of the human stomach. Its colonization is so complex, prevalent, and long-lasting that Blaser is convinced H. pylori deserves a place among the more than 200 commensals—microbes that reside, more or less harmlessly, in the skin, eyes, nose, mouth, gut, and genitals of the human ecosystem. He views the chronic inflammation it produces as a reservoir of disease-fighting cells rather than just a source of cancer-prone lesions.

"I now see H. pylori as the normal flora of the stomach," he says. "And one of the roles of the normal flora is to prime the immune system against exogenous organisms."

Blaser believes there's enough evidence for the bacterium's beneficial effects to be cautious in treating it. He has long emphasized the inverse relationship between H. pylori infection and reflux disease as well as esophageal cancer, the fastest growing malignancy in the United States. When the microbe was more prevalent, he says, it could be counted on to curb stomach acid. Less acid meant less acid reflux, and less acid reflux meant fewer esophageal lesions. "For the first time in history, you have 40- and 50-year-olds who are producing full amounts of acid," he says. "The question now is, what are we going to do with all the [asymptomatic] people? Before the connection with reflux, people thought the only good H. pylori was a dead one."

Some people still think that. David Graham argues that H. pylori's protection is pathological. Acid secretion is dramatically suppressed, for example, in gastric cancer, which in the early 1900s was the most common cancer in the United States. "It's like saying smoking protects against the diseases of old age," he says. And while rates of esophageal cancer are rising quickly, it still makes up only 1 percent of the cancers diagnosed in the United States each year. Graham also maintains H. pylori can't be called a commensal just because so few carriers develop symptoms of illness.

"Only 10 percent of the people who harbor tuberculosis get sick from it; only 10 percent of the people who harbor syphilis get sick," he says. "We ought to be working to eradicate H. pylori from mankind."

The debate is somewhat academic. Global screening and extermination programs are impractical, and efforts to produce a vaccine have yet to succeed.

H. pylori, like other parasites, is succumbing to modern hygiene: Water is less likely to be contaminated with stool, children are less likely to share beds, and most kids get several courses of antibiotics before the first grade. "In a generation or two in this country, it's not going to matter, except to immigrants," says Berg. "H. pylori is dying out."

But in other countries, Berg says, the bacterium poses a greater public-health threat. In parts of Asia, for example, almost everyone carries the most virulent strains of the bug, and gastric cancer is a leading killer. H. pylori's role in the rampant diarrheal diseases of Africa is still uncertain. Some observers claim

H. pylori may aid those diseases by reducing stomach acid, the main barrier to food-borne and waterborne infections. It's now clear that while infections of the upper stomach do reduce the acidity of gastric juices, infections of the lower stomach may actually increase stomach acid by destroying regulatory cells that limit how low the pH there can go. The differences between infections at the two sites—as well as the age, diet, and genes of the host—influence how severe an infection becomes.

"One of the challenges of H. pylori research is to figure out why so many people carry it but only 10 to 20 percent get sick," Berg says.

Until more is known about the bacterium's mechanisms of action, neither its role in human innards nor the consequences of its passing can be fully appreciated. But that's true of every other microbe that makes its home in the human body, says Blaser. Even Graham admits as much. "Good or bad," he says, "it's going to be a difficult problem to understand."